INOSINE-5 -Carboxylates

ABSTRACT

Inosine-5&#39;&#39;-carboxylates represented by the formula   WHEREIN R1 is loweralkyl, lowerhaloalkyl, or lowerhydroxyalkyl and R2 and R3 each are hydrogen or acyl, or R2 and R3 when taken together form an isopropylidene or benzylidene moiety, and the pharmaceutically acceptable salts thereof. The compounds of this invention are useful in preparing the corresponding amides which are useful as sedatives and hypotensive agents.

United States Patent 1 Prasad et al.

[ INOSINE-S -CARBOXYLATES [75] Inventors: Raj Nandan Prasad,Pierrefonds,

Quebec, Canada; Herman Hal Stein,

Skokie, lll.

[73] Assignee: Abbott Laboratories, Chicago, Ill. [22] Filed: Feb. 12,1973 [21 Appl. No.: 331,398

52 Us. (:1. 260/21l.5 R, 424/180 51 Int. Cl com 51/54 [58] Field ofSearch I. 260/21 1.5 R

Primary ExaminerJohnnie R. Brown Attorney, Agent, or FirmRobert L.Niblack; Joyce R. Krei; Vincent A. Mallare Dec. 10, 1974 [57] ABSTRACTInosine-S '-carboxylates represented by the formula wherein R isloweralkyl, lowerhaloalkyl, or lowerhydroxyalkyl and R and R each arehydrogen or acyl, or R and R when taken together form an isopropylideneor benzylidene moiety, and the pharmaceutically acceptable saltsthereof. The compounds of this invention are useful in preparing thecorresponding amides which are useful as sedatives and hypotensiveagents- 6 Claims, No Drawings diodo.

1 INOSINE-S-CARBOXYLATES DETAILED DESCRIPTION OF THE INVENTION Thisinvention relates to inosine-'-carboxylates, and to methods of preparingthe compounds.

The compounds of this invention are represented by the formula whereinR, is loweralkyl, lowerhaloalkyl, or lowerhydroxyalkyl and R and R eachare hydrogen or acyl, or R and R when taken together form anisopropylidene or benzylidene moiety, and the pharmaceuticallyacceptable salts thereof. The compounds of this invention are useful inpreparing the corresponding amides which are useful as sedatives andhypotensive-agents.

The term loweralkyl as used herein, refers to both straight and branchedchain alkyl radicals containing from 1 to 6 carbon atoms, includingmethyl, ethyl, npropyl, iso-propyl, n-butyl, sec-butyl, tert-butyl,isobutyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl and the like.

The term acyl" refers to acetyl, propionyl, butyryl and the like.

The term halo" includes chloro, fluoro, bromo, and

The term pharmaceutically acceptable salts refers to either the nontoxicacid addition salts prepared by reacting the ester with an appropriateorganic or inorganic acid, or by utilizing an acid addition salt of theappropriate intermediate. Representative salts include thehydrochloride, hydrobromide, sulfate, bisulfate, acetate, valerate,oleate, laurate, borate, benzoate, lactate, phosphate, tosylate,citrate, maleate, succinate, tartrate, napsylate and the like, as wellas the cationic salts such as the sodium, potassium, aluminum, cal cium,magnesium, barium, ammonium and substitute ammonium salts. I

The term substituted ammonium" includes, but is not limited, to methylammonium, diethyl ammonium, benzyl ammonium, triethanol ammonium, andthe like.

The compounds of this invention are useful as intermediates in thepreparation of the corresponding amides which are useful as sedativesand hypotensive agents.

Generally speaking, the compounds of this invention are prepared from2',3'-isopropylidene inosine by the following route:

2 (HI (IHI r) 1 K AT 3 0 110- 0 no- 0 1? Xv o o 01 1 on {II in lnionsoolz 11 no i T RIO-U o K) on on The following examples furtherillustrate this invention EXAMPLE 1 2',3'-0-IsopropylideneInosine-5'-Carboxylic Acid Chromium trioxide (12.0 g, 0.120 mole;freshly washed with glacial acetic acid) was added, portionwise, to astirred solution of isopropylidene inosine (32.0 g; 0.0104 mole) inglacial acetic acid (500 ml.) at room temperature. Within a few hours,the dark reaction mixture spontaneously warmed up to 35C. No attempt wasmade to control the temperature. The reaction mixture was stirred atroom temperature for three days. The crude acid was filtered, washedwith cold acetic acid, followed by ether and finally the residue waswashed with plenty of cold water to give a colorless solid. The solid,after drying over P 0 in vacuo at C. for 16 hours, was pure enough forthe subsequent reactions. Yield 24.0 g. (72%); mp. 260 dec; R, 0.30(7:211 Isopropanol:H O:NH OH); characteristic IR band at 1720 cm.

EXAMPLE 2 INO SINE- S CARBOXYLIC ACID A mixture of 2',3-O-isopropylidene inosine-5- carboxylic acid (6.4 g; 0.020 mole),concentrated HCl (30 ml.) and water (300- ml.) was kept at 60C. for 30minutes and then cooled to 0C. The clear reaction mixture was brought topH 2.5-3.0 by adding NaI-ICO solution and the product was filtered andwashed with cold water to yield 4.4 g. (79%) of inosine-5'-carboxylicacid, mp. 170-175C; R, 0.2l;(7:2:l isopropanol:- H O:NH OH);characteristic IR band at 1720 cm".

EXAMPLE 3 Inosinc-5'-( B-Chloroethyl) Carboxylate Thionyl chloride (4ml.) was added dropwise to a suspension of inosine-5'-'carboxylic acid(5.7 g; 0.0202

, mole) in 2-chloroethanol ml) at 5'l0C. After the stirred ether (300ml.). The ether was decanted carefully and the viscous layer wastriturated with some more ether. The solid, so separated, was dissolvedin 2 cold water (30 ml.) and the clear aqueous solution was basifiedwith saturated aqueous NaHCO solution. The precipitate was filtered off,washed successively with water, acetone and ether and dried in vacuumfor 4 hours over P at 65C.

Yield 5.5 g (80%); mp 177180. Infra-red spectra showed thecharacteristic band at 1750 cm), R, 0.35 (43:7 n-butanol: H O).

EXAMPLE 4 Inosine5-carboxylic acid, ethyl ester is prepared according tothe method of Example 3 by reacting ethyl alcohol withinosine-5-carboxylic acid.

EXAMPLE 5 lnosine-5'-carboxylic acid, methyl ester is prepared accordingto the method of Example 3 by reacting methyl alcohol withinosine-5'-carboxylic acid.

EXAMPLE 6 Inosine-5-carboxylic acid, n-propyl ester is preparedaccording to the method of Example 3 by reacting npropyl alcohol withinosine-5'-carboxylic acid.

EXAMPLE 7 lnosine-5-carboxylic acid, iso-propyl ester is pre paredaccording to the method of Example 3 by reacting iso-propyl. alcoholwith inosine-5-carboxylic acid.

EXAMPLE 8 lnosine-5-carboxylic acid, n-butyl ester is prepared accordingto the method of Example 3 by reacting nbutyl alcohol withinosine-5'-carboxylic acid.

EXAMPLE 9 lnosine-5-carboxylic acid, sec-butyl ester is preparedaccording to the method of Example 3 by reacting sec-butyl alcohol withinosine-5'-carboxylic acid.

EXAMPLE l0 lnosine-5-carboxylic acid, tert-butyl ester is preparedaccording to the method of Example 3 by reacting tert-butyl alcohol withinosine-S-carboxylic acid.

EXAMPLE ll Inosine-5'-carboxylic acid, n-pentyl ester is preparedaccording to the method of Example 3 by reacting npentyl alcohol withinosine-5'-carboxylic acid.

EXAMPLE l2 lnosine-5-carboxylic acid, iso-pentyl ester is preparedaccording to the method of Example 3 by reacting iso-pentyl alcohol withinosine-5'-carboxyli c acid.

EXAMPLE l3 lnosine-5'-carboxylic acid, neo-pentyl ester is preparedaccording to the method of Example 3 by reacting neo-pentyl alcohol withinosine-S-carboxylic acid.

EXAMPLE l4 Inosine-5'-carboxylic acid, n-hexyl ester is preparedaccording to the method of Example 3 by reacting nhexy] alcohol withinosine-5-carboxy]ic acid.

EXAMPLE l5 lnosine-S'-carboxylic acid, hydroxycthyl ester is prcparedaccording to the method of Example 3 by reacting hydroxyethyl alcoholwith inosinc-S'-carboxylic acid.

EXAMPLE l6 Inosine-5-carboxylic acid, iodomethyl ester is preparedaccording to the method of Example 3 by reacting iodomethyl alcohol withinosine-5'-carboxylic acid.

We claim: 1. A compound of the formula 5'-carboxylic acid, chloroethylester.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION OPATENT N0. 1' 3,853,846

DATED December 10, 1974 INVENTOR(S) Raj Nandan Prasad and Herman HalStein It is certified that error appears in the ab0veidentified patentand that said Letters Patent are hereby corrected as shown below:

In the title:

Delete "INOSINE-S-CARBOXYLATES" 0 and substitute therefor--INOSINE5'-CARBOXYLATES-- A In Celumn 2, first line of formulae, patentline 5,

delete the "H between the two formulas and substitute O therefor "fiSigned and Scaled this I I twenty-fifth D3) 0f November 1975 SEALArrest.

RUTH C. MAISON C. MARSHALL DANN 411851711X 1/ ('mnmixxl'mwr uj'Patenrsand Trademarks

1. A COMPOUND O THE FORMULA
 2. A compound of claim 1 wherein R2 and R3each are hydrogen.
 3. A compound in accordance with claim 2 wherein R1is loweralkyl.
 4. A compound in accordance with claim 2 wherein R1 ishydroxyalkyl.
 5. A compound in accordance with claim 2 wherein R1 ishaloalkyl.
 6. A compound in accordance with claim 5,inosine-5''-carboxylic acid, chloroethyl ester.